Chemokines (chemoattractant cytokines) are a family of homologous serum proteins of between 7 and 16 kDa, which were originally characterized by their ability to induce migration of leukocytes. Most chemokines have four characteristic cysteines (Cys), and depending on the motif displayed by the first two cysteines, they have been classified into CXC or alpha, CC or beta, C or gamma, and CX3C or delta chemokine classes. Two disulfide bonds are formed between the first and third cysteines and between the second and fourth cysteines. Clark-Lewis and co-workers reported that, at least for IL-8, the disulfide bridges are critical for chemokine activity (Clark-Lewis et al., J. Biol. Chem. 269:16075-16081, 1994). The only exception to the four cysteine motif is lymphotactin, which has only two cysteine residues. Thus, lymphotactin retains a functional structure with only one disulfide bond.
In addition, the CXC, or alpha, subfamily has been divided into two groups depending on the presence of the ELR motif (Glu-Leu-Arg) preceding the first cysteine: the ELR-CXC chemokines and the non-ELR-CXC chemokines (see, e.g. Clark-Lewis, supra, and Belperio et al., “CXC Chemokines in Angiogenesis,” J. Leukoc. Biol. 68:1-8, 2000).
ELR-CXC chemokines, such as IL-8, are generally strong neutrophil chemoattractants while non-ELR chemokines, such as IP-10, and SDF-1, predominantly recruit lymphocytes. CC chemokines, such as RANTES, MIP-1-alpha, MCP-1, generally function as chemoattractants for monocytes, basophils, eosinophils, and T-cells but not neutrophils. In general, chemokines are chemotactic agents that recruit leukocytes to the sites of injuries.
SDF-1
Stromal cell-derived factor-1 (SDF-1 or CXCL12) is a CXC chemokine that demonstrates in vitro activity with respect to lymphocytes and monocytes but not neutrophils. It is a highly potent in vivo chemoattractant for mononuclear cells. SDF-1 has been shown to induce intracellular actin polymerization in lymphocytes, and to induce a transient elevation of cytoplasmic calcium in some cells.
MIP-1α
Macrophage inflammatory protein-1α (MIP-1α, MIP-1-alpha or CCL3) is a factor produced by macrophages in response to their stimulation by bacterial endotoxins. It activates neutrophils, eosinophils, and basophils and appears to play a role in inflammation. Additionally, it is especially potent as a basophil agonist, and appears to act through a rapid rise in intracellular calcium, and causes the release of histamine, sulfido-leukotrienes, and also plays a role in chemotaxis. MIP-1-alpha may also act to inhibit stem cell proliferation.
Chemokine Receptors
The receptors for chemokines are G-protein coupled seven-transmembrane receptors. Based on the chemokine class they bind, the receptors have been named CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 (all of which bind CXC chemokines); CCR1 through CCR9 (all of which bind CC chemokines); XCR1 (which binds the C chemokine, Lptn); and CX3CR1 (which binds the CX3C chemokine, fractalkine or neurotactin). (See Table 1.)
The chemokines and their receptors have received increasing attention in the last few years. In addition to their role in HIV pathogenesis, it is now clear that chemokines participate in many pathological conditions such as inflammation and diseases or conditions associated with autoimmune responses. They also play a very important role in normal homeostasis, including lymphoid development and migration. Further, they play a role in the growth of bones. As a result of their role in various physiological processes and pathological conditions and diseases, chemokines have many important potential therapeutic applications.
TABLE 1Chemokine receptorsHuman chemokine ligandsCXCR1IL-8, GCP-2CXCR2IL-8, GCP-2, Gro α, Gro β, Gro γ, ENA-78, PBPCXCR3MIG, EP-10, I-TACCXCR4SDF-1/PBSFCCR1MEP-1 α, MIP-1 β, RANTES, HCC-1, 2, 3, and 4CCR2MCP-1, MCP-2, MCP-3, MCP-4CCR3Eotaxin-1 eotaxin-2, MCP-3CCR4TARC, MDC, MIP-1 α, RANTESCCR5MIP-1 α, MIP-1 β, RANTESCCR6MIP-3 α/LARCCCR7MP-3 β/ELC, 6Ckine/LCCCR8I-309CCR9TECKCCR10CCL27, CCL28(hMEC)
Certain agonists of CXCR4 have been described in International Publication No. WO 01/76615 A2 entitled “CXCR4 Agonist Treatment of Hematopoietic Cells” (PCT/CA01/00540). Certain antagonists of CXCR4 have been described in International Publication No. WO 01/85196 A2 entitled “CXCR4 Antagonist Treatment of Hematopoietic Cells” (PCT/CA01/00659. Both PCT publications are hereby incorporated by reference herein, including any drawings, figures and tables.